This RSDA will support extension of the applicant's research program in geriatric mood disorders, a heterogeneous group of illnesses that represent an expanding public health burden. This program focuses on the significance of the heterogeneity of geriatric mood disorders for response to pharmacotherapy. The applicant's accomplishments have included; 1) studies of response to nortriptyline; these investigations have involved development of an acute treatment paradigm which accounts for the wide interindividual pharmacokinetic differences among geriatric patients and tests hypothesized differences in concentration-effect relationships in subgroups defined y cognitive capacity and brain morphology; 2) preliminary work in geriatric patients with mania, including contributions to assessment methodology, neuroradiologic characterization, and preliminary description of acute response to naturalistic treatment. This application brings together the applicant's background and record of productivity, the uniquely large clinical population available for study, the strructure of the Developing Clinical Research Center for Geriatric Affective Disorders and its longitudinal research perspective, an the proximity of internationally known basic science laboratories and research groups studying dementing disorders and psychiatric disorders in multidisciplinary collaboration. The short-term goals are to continue studies of acute nortriptyline treatment in geriatric major depression, and to extend this paradigm to sertraline in geriatric depression and to both lithium and valproate in geriatric mania. The applicant also will develop increased depth of knowledge in neuropsychology and neuroimaging, through ongoing collaborative relationships that foster intellectual growth as well as productivity. This program will enhance the applicants's teaching role as a mentor for medical students, psychiatric residents, and NIMH research fellows in geriatric psychiatry. The long-term goals are to develop randomized concentration-comparison studies using nortriptyline and lithium in geriatric patients; to test findings from acute treatment paradigms in studies of continuation and maintenance treatment; and to examine relationship between acute response and long-term outcomes.